Case Presentation

A 64-year-old woman presented to her primary care physician with a subacute history of worsening diffuse abdominal pain with intermittent bilious vomiting and non-bloody diarrhea, with no aggravating and alleviating factors. Her past medical history was notable for class III obesity (body mass index 47.1 kg/m2), hypertension, anxiety, and hypothyroidism (on levothyroxine). She had no personal or family history of liver disease, obstructive sleep apnea, myeloproliferative disease, gallbladder cancer, or other malignancy. She reported no alcohol use, tobacco use, recent herbal supplement or mushroom ingestions, medication changes, intravenous drug use, recent travel, illnesses, or sick contacts. Evaluation in the PCP’s office was notable for hypovolemia attributed to poor oral intake and she was sent to the emergency department for fluid resuscitation.

On initial ER evaluation, she had diffuse abdominal tenderness, a dusky-appearing right hand, and a diminished radial pulse. Initial laboratory studies revealed erythrocytosis (hemoglobin 19.8 g/dL) and abnormal liver chemistries (aspartate aminotransferase [AST] 1,280 U/dL, alanine aminotransferase [ALT] 1,750 U/dL, alkaline phosphatase 225 U/dL, total bilirubin 4.5 mg/dL, the international normalized ratio [INR] 1.88). She also had leukocytosis (white blood cell 28.5 x 103/uL) and concomitant acute kidney injury with serum creatinine 1.9 mg/dL from a baseline of 0.9 mg/dL. She was admitted for sepsis complicated by acute liver injury and started on IV fluids and broad-spectrum antibiotics. Blood and urine cultures were negative, as were serologies for acute viral hepatitis. A mildly elevated anti-nuclear (ANA) antibody titer (1:80) was noted. In the setting of new erythrocytosis, she was found to have elevated serum erythropoietin of 64 mU/mL (reference range: 2.6-18.5 mU/mL). Abdominal ultrasound with doppler revealed diminished flow in the main and right portal veins, perihepatic ascites, and curvilinear calcification noted along the gallbladder fossa, suggestive of porcelain gallbladder. Non-contrast abdominal magnetic resonance imaging (MRI) showed caudate lobe prominence but no obvious hepatic vein thrombosis. Given the concern for polycythemia vera with Budd-Chiari syndrome, therapeutic phlebotomy and contrast-enhanced computed tomography were planned.

Unfortunately, the patient developed acute liver failure, disseminated intravascular coagulation, pulmonary hemothorax, and refractory septic shock over the next five days. The patient ultimately died from multisystem organ failure. On autopsy, she had multiple thromboembolic complications noted including pulmonary artery and hepatic venous thrombosis with intrahepatic venous extension. Additionally, an arterial and venous duplex ultrasound of her right extremity revealed an occlusive thrombus of the superficial basilic and cephalic veins. Histology revealed evidence of hepatocellular necrosis, gallbladder adenocarcinoma with calculous cholecystitis, and empyema. Bone marrow biopsy with JAK2 genetic testing was sent due to clinical suspicion of polycythemia vera-associated hepatic vein thrombosis, revealing a V617F point mutation.

Discussion

We present a patient with a common presentation of nonspecific upper and lower gastrointestinal symptoms who was found to have several risk factors for thromboembolic disease, Budd-Chiari syndrome, and ultimately passed away from its complications. This case highlights how the patient’s comorbid conditions, namely polycythemia vera, gallbladder carcinoma, and obesity, may have contributed to her hypercoagulable state and increased her risk for Budd-Chiari syndrome, as described in the table.

Budd-Chiari syndrome is a rare disease with an estimated incidence of 0.1 to 10 per million patients annually1. Its hallmark is hepatic venous outflow obstruction, causing venous congestion that stretches the liver capsule. The most common risk factor for Budd-Chiari syndrome is a hypercoagulable state, often secondary to myeloproliferative disorders, malignancy, hepatic lesions, pregnancy, or oral contraceptive use. Manifestations of Budd-Chiari syndrome include ascites, acute kidney injury, hepatic encephalopathy, and acute liver failure. Budd-Chiari syndrome can be diagnosed with visualization of the thrombus using ultrasonography with color doppler. Treatment includes reducing thrombus propagation with anticoagulants, as well as addressing the underlying cause. Definitive treatment includes thrombolytics and percutaneous transluminal angioplasty to relieve the obstruction as well as transjugular intrahepatic portosystemic shunts (TIPS) to reroute blood flow.¹

The largest contributory factor to the patient’s hypercoagulable state and Budd-Chiari syndrome was likely polycythemia vera, undiagnosed before the presentation. Polycythemia vera is a myeloproliferative disorder caused by the neoplastic proliferation of hematopoietic stem cells.² It is characterized primarily by increased red blood cell production, and secondary white blood cell and platelet production. Diagnosis requires two of the following major criteria: Hgb > 16.5g/dL in men or Hgb > 16g/dL in women, hypercellularity of the bone marrow with trilineage growth, and JAK2 V617F mutation. Polycythemia vera causes a hypercoagulable state largely due to hyperviscosity from polycythemia and secondary thrombocytosis. Patients with polycythemia vera and JAK2 mutations comprise the largest subset of patients who develop Budd-Chiari syndrome, comprising an estimated 59% of cases.³ Management of polycythemia vera requires aggressive phlebotomy to achieve target hematocrit levels below 45%, at times necessitating additional cytoreductive drugs. For older patients with JAK2^V617F allele burden, controlling hematocrit levels and preventing cardiovascular risk factors are imperative in mitigating thrombosis risk.

Gallbladder carcinoma, also undiagnosed before the time of our patient’s presentation, is associated with an increased risk of thromboembolic disease. The overall incidence of incidental gallbladder carcinoma has been estimated to be as low as 0.51%.⁴ Gallbladder carcinoma-related thrombotic events have been reported in cases of non-bacterial thrombotic endocarditis as well as cerebral vascular thrombus, portal vein tumor thrombus, and common bile duct tumor thrombosis secondary to hepatocellular carcinoma.⁴

Additionally, obesity also contributed to our patient’s increased hypercoagulability risk. The systemic inflammation of obesity is thought to be associated with a higher risk for both thromboembolic disease and gallbladder carcinoma.⁵ Obesity remains a risk factor often overlooked but known to confer risk for myeloproliferative disorders, with weight loss as the main behavioral modification to ensure the prevention of associated thromboembolic risk.

This clinical case highlights the importance of a high index of suspicion for testing in the appropriate patient, expedited workup, and timely diagnosis of Budd-Chiari syndrome and its risk factors. Given that diagnosis of polycythemia vera primarily involves a routine complete blood count (CBC), the patient may have received an earlier diagnosis and treatment of polycythemia vera, had she received regular primary care with routine blood work. In addition, this patient presented in a late stage of Budd-Chiari syndrome, after five days of persistent gastrointestinal symptoms, and quickly succumbed to the complications of fulminant liver failure. Had the patient presented earlier in her course, laboratory analysis may have revealed elevated aminotransferases, leukocytosis, and erythrocytosis characteristic of Budd-Chiari syndrome, and may have expedited access to life-saving treatment, including hospitalization and inpatient specialty consult for live-saving treatment such as angioplasty, thrombolytic therapy, or liver transplantation.

Our case emphasizes the importance of an internist’s approach to expedited evaluation in patients in whom there is a high index of suspicion for Budd-Chiari syndrome. In a presentation of multiple days of nonbilious emesis and infectious gastrointestinal symptoms in a clinically ill patient and laboratory findings concerning for polycythemia and liver injury, a high index of suspicion for Budd-Chiari syndrome with expedited imaging for diagnosis may be lifesaving.